5jm4
From Proteopedia
Crystal structure of 14-3-3zeta in complex with a cyclic peptide involving an adamantyl and a dicarboxy side chain
Structural highlights
Function1433Z_HUMAN Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner.[1] [2] [3] [4] [5] Publication Abstract from PubMedMacrocyclic peptides can interfere with challenging biomolecular targets including protein-protein interactions. Whereas there are various approaches that facilitate the identification of peptide-derived ligands, their evolution into higher affinity binders remains a major hurdle. We report a virtual screen based on molecular docking that allows the affinity maturation of macrocyclic peptides taking non-natural amino acids into consideration. These macrocycles bear large and flexible substituents that usually complicate the use of docking approaches. A virtual library containing more than 1400 structures was screened against the target focusing on docking poses with the core structure resembling a known bioactive conformation. Based on this screen, a macrocyclic peptide 22 involving two non-natural amino acids was evolved showing increased target affinity and biological activity. Predicted binding modes were verified by X-ray crystallography. The presented workflow allows the screening of large macrocyclic peptides with diverse modifications thereby expanding the accessible chemical space and reducing synthetic efforts. Structure-Based Design of Non-natural Macrocyclic Peptides That Inhibit Protein-Protein Interactions.,Kruger DM, Glas A, Bier D, Pospiech N, Wallraven K, Dietrich L, Ottmann C, Koch O, Hennig S, Grossmann TN J Med Chem. 2017 Nov 9;60(21):8982-8988. doi: 10.1021/acs.jmedchem.7b01221. Epub , 2017 Oct 27. PMID:29028171[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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